NOT gated T cells that selectively target EGFR and other widely expressed tumor antigens.

Autor:	Oh J; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Kirsh C; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Hsin JP; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Radecki KC; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Zampieri A; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Manry D; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Ando Y; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Miller S; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Chan J; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., McLeod E; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Cunningham KM; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Wong LM; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Xu H; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA., Kamb A; A2 Biotherapeutics; 30301 Agoura Rd., Agoura Hills 91301, CA, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 May 07; Vol. 27 (6), pp. 109913. Date of Electronic Publication: 2024 May 07 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.109913
Abstrakt:	Here, we show that a NOT gated cell therapy (Tmod) can exploit antigens such as epidermal growth factor receptor (EGFR) and human leukocyte antigen-E (HLA-E) which are widely expressed on cancer cells. Noncancerous cells-despite high expression of these antigens-are protected from cytotoxicity by the action of an inhibitory receptor ("blocker") via a mechanism that involves blocker modulation of CAR surface expression. The blocker is triggered by the product of a polymorphic HLA allele (e.g., HLA-A∗02) deleted in a significant subset of solid tumors via loss of heterozygosity. Moreover, Tmod constructs that target mouse homologs of EGFR or HLA-E for activation, and a mouse-equivalent of HLA-A∗02 for inhibition, protect mice from toxicity caused by the CAR alone. The blocker also controls graft vs. host response in allogeneic T cells in vitro , consistent with the use of Tmod cells for off-the-shelf therapy without additional gene-editing. Competing Interests: All authors are/were employees and shareholders of A2 Biotherapeutics, Inc. A.K. is a board member of A2 Biotherapeutics. J.O., H.X., and A.K. are inventors of PCT/US2021/046733 (published as WO 2022/040444); A.K. is an inventor of PCT/US2020/064607 (published as WO 2021/119489) and US Patent No. 11,254,726. (© 2024 A2 Biotherapeutics.)
Databáze:	MEDLINE
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